Autoimmune hepatitis

• Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver in which the immune system attacks hepatocytes. It is uncommon, more frequent in women, and can present at almost any age.
• There is no single diagnostic test. The diagnosis rests on a characteristic pattern of blood tests (transaminases and immunoglobulin G), autoantibodies, compatible liver histology, and the exclusion of other causes of hepatitis.
• Baseline cirrhosis is present in about a quarter to a third of adults at the time of diagnosis, because the disease is often silent.
• First-line treatment is an induction course of glucocorticoid (prednisolone or budesonide) with azathioprine, followed by maintenance, usually for years.
• Sustained biochemical remission (normal alanine aminotransferase and immunoglobulin G) for at least two years is the gateway to considering drug withdrawal, although relapse is common.

By the end of this page you should be able to:

1. Define autoimmune hepatitis and distinguish its two types.
2. State who is affected and which other autoimmune diseases cluster with AIH.
3. Interpret liver tests, autoantibodies and liver histology in suspected AIH.
4. Exclude viral hepatitis, Wilson disease and drug-induced liver injury.
5. Work through the Paris criteria for overlap syndromes and the IAIHG diagnostic scores.
6. Plan induction, maintenance and withdrawal, including doses and monitoring.
7. Recognise complications, prognosis and the need for hepatocellular carcinoma surveillance, including in pregnancy and low-resource settings.

Classification is by the pattern of autoantibodies rather than by pathology. Autoimmune hepatitis type 1 (AIH-1) is marked by antinuclear antibodies, smooth muscle antibodies and sometimes soluble liver antigen/liver pancreas antibodies. Autoimmune hepatitis type 2 (AIH-2) is marked by anti-liver kidney microsomal type 1 and anti-liver cytosol type 1 antibodies, usually in children or young adults. Roughly one in five patients is seronegative for the three classical antibodies despite otherwise typical disease. ^[1][3] The type 1/type 2 labels are still widely used, including in KASL 2022, although HASL 2024 and EASL 2025 no longer recommend subclassifying AIH by autoantibody profile. ^[3][4]

AIH is uncommon but increasing in incidence worldwide. Pooled estimates give a global annual incidence of about 1.37 per 100,000 and a prevalence of about 17.44 per 100,000. ^[3] A female predominance is consistent: across large studies women are affected roughly three to six times more often than men, depending on the region. ^[1][3][4]

Age at onset is bimodal in several cohorts, with peaks in adolescence and again around the sixth decade; other regions show a single peak in the sixth or seventh decade. ^[3] About a third of adults and 40 to 50 percent of children already have cirrhosis at the time of diagnosis, often because the disease is silent or intermittently active for years. ^[4] Between a quarter and 37 percent of adults are completely asymptomatic when first diagnosed, while HASL 2024 describes most patients as asymptomatic or with only nonspecific symptoms. ^[3][4]

The cause is unknown. The working model is loss of self-tolerance to hepatocyte antigens in a genetically susceptible host, triggered by an environmental insult. Susceptibility genes differ by population, but variants of human leukocyte antigen DRB1, particularly DRB103 and DRB104, are repeatedly associated with disease and with its natural course. ^[3] Concurrent autoimmune disease is common, falling in the broad range of 14 to 44 percent across studies. ^[3]

The most frequent extrahepatic associations are:

• Autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease), in roughly 10 to 23 percent.
• Rheumatoid arthritis, in about 2 to 4 percent.
• Sjögren syndrome, in about 3 to 7 percent.
• Inflammatory bowel disease, in about 2 to 11 percent.
• Systemic lupus erythematosus, celiac disease and type 1 diabetes mellitus, less commonly.
• Type 2 AIH in particular clusters with type 1 diabetes, autoimmune thyroid disease and autoimmune skin disease. ^[3][4]

Screening for thyroid disease is recommended at diagnosis, and patients should be assessed for celiac disease. ^[1][4]

The liver injury in AIH is T-cell mediated. Autoreactive CD4 and CD8 T cells recognise hepatocyte antigens, leading to cytokine-driven necroinflammation that concentrates at the portal tract interface with the lobule. Interface hepatitis (piecemeal necrosis) is the morphological consequence. Serum immunoglobulin G rises, often markedly, because B-cell responses are also activated and help amplify the inflammatory signal. Over time, repeated necroinflammation progresses to fibrosis and then cirrhosis, unless immunosuppression suppresses the activity. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis changes are present in 17 to 30 percent of adult patients and are associated with worse outcomes. ^[2][3]

The spectrum is wide, from entirely silent to acute liver failure.

Asymptomatic. Between a quarter and 37 percent of adults have no symptoms and are found on routine blood testing. Their transaminases are raised and their immunoglobulin G is often elevated, but usually less than in symptomatic patients. Their long-term survival is broadly comparable with symptomatic patients when treated. ^[3]

Chronic presentation. The most frequent form is chronic hepatitis with non-specific symptoms: fatigue, anorexia, nausea, right upper quadrant discomfort, arthralgia of the small joints and amenorrhoea. Low-grade fever is less common. Splenomegaly and hepatomegaly may be found on examination.

Acute or acute-severe presentation. Acute onset or an acute flare of undiagnosed disease accounts for roughly a quarter to half of cases, depending on the cohort. ^[2][4] Acute-severe AIH is defined by jaundice, an international normalised ratio of 1.5 to 2, and no hepatic encephalopathy; acute liver failure with encephalopathy develops in 3 to 6 percent of patients. ^[3] In acute-onset disease, antinuclear antibody is negative in up to 29 to 39 percent and immunoglobulin G is normal in 25 to 39 percent, so the disease is easy to miss. ^[3]

Examination. Look for stigmata of chronic liver disease: jaundice, spider naevi, palmar erythema, ascites, splenomegaly and a firm liver edge. Signs of the extrahepatic autoimmune associations (goitre, vitiligo, joint changes) may be present.

Differential (feature that separates each candidate):

AIH-type disease can also be triggered by drugs, supplements and herbals (drug-induced autoimmune-like hepatitis, below). ^[3][4]

First-line blood tests. Alanine aminotransferase and aspartate aminotransferase are raised, usually markedly, with cholestatic enzymes normal or only mildly raised. Bilirubin may be normal or raised. Total globulin or immunoglobulin G is raised in about 85 percent of patients. ^[4] Aminotransferase values fluctuate and may normalise spontaneously even while inflammation continues on biopsy, which underestimates disease if taken at face value.

Serology. Antinuclear antibody and smooth muscle antibody by indirect immunofluorescence are the first screening tests; anti-liver kidney microsomal type 1 and anti-liver cytosol type 1, soluble liver antigen/liver pancreas and perinuclear anti-neutrophil cytoplasmic antibody follow when the first screen is negative. ^[3][4] Clinically significant titres are at least 1:40 in adults (lower in children). Soluble liver antigen/liver pancreas antibody is highly specific but insensitive, and characterises patients who often need long-term immunosuppression. ^[4] Antimitochondrial antibody is positive in about 5 percent of AIH patients without changing treatment response or mortality. ^[4]

Non-invasive fibrosis. Transient elastography is useful for advanced fibrosis after inflammatory activity has been controlled; values within the first three months of treatment are confounded by inflammation. ^[2]

Liver biopsy. This is a prerequisite for the diagnosis whenever it is safe. It confirms interface hepatitis, characterises severity and stage, excludes mimics (bile duct injury suggests overlap, granulomas another diagnosis), and documents fibrosis. An adequate core is at least 1.5 cm with 6 to 8 portal tracts, taken with a 16 gauge or wider needle. ^[4] If non-invasive sampling is used, the histological pattern is missed.

A video of how to read a core would say: look for a dense lymphoplasmacytic portal infiltrate, interface hepatitis, plasma cells and rosettes. These are the classical picture of chronic AIH, though none is pathognomonic. ^[3][4]

There is no single confirmatory test. The International Autoimmune Hepatitis Group (IAIHG) criteria codify the constellation. The 1999 revised original score and the 2008 simplified score are both in use; the simplified system has higher specificity (about 90 percent), the revised system higher sensitivity, so a low simplified score should be reassessed with the revised system. ^[2][3][4]

The table is retained for historical comparison. KASL 2022 still distinguishes the two types, whereas HASL 2024 (and EASL 2025) no longer recommend this subclassification because subtype alone does not reliably predict outcome or response. ^[3][4]

Anti-soluble liver antigen/liver pancreas antibody occurs in 20 to 30 percent of both types and is the most specific marker for AIH. Perinuclear anti-neutrophil cytoplasmic antibody occurs in 20 to 96 percent of type 1 and can be the only marker. ^[3][4]

AIH-type disease with PSC overlap is diagnosed from typical AIH features plus absence of antimitochondrial antibody plus cholangiographic or histological evidence of PSC. ^[3][4]

An overlap syndrome is AIH together with primary biliary cholangitis, primary sclerosing cholangitis or, more rarely, IgG4-related cholangitis. AIH-PBC overlap is found in 7 to 12 percent of AIH patients and often presents simultaneously; AIH-PSC is rarer in the East and more often develops with AIH diagnosed first and PSC later. ^[3] Management follows the predominant phenotype: in AIH-PBC, ursodeoxycholic acid together with immunosuppressive therapy, starting with ursodeoxycholic acid first when PBC features predominate and adding immunosuppression according to response. ^[3][4] All children and adolescents with AIH should have MRCP at baseline to exclude AIH-PSC overlap, regardless of the cholestatic enzymes; in adults this should be reserved for those with cholestasis and negative PBC antibodies. ^[4]

The diagnosis of AIH requires the compatible histology and exclusion of viral, hereditary, metabolic, cholestatic and drug-induced diseases. ^[1] Mandatory steps at diagnosis:

1. Viral serology: hepatitis A IgM, hepatitis B surface antigen and core antibody, hepatitis C antibody/RNA, and hepatitis E where appropriate.
2. Wilson disease screening: caeruloplasmin, and copper studies if risk.
3. Haemochromatosis indices.
4. Alpha-1 antitrypsin.
5. Autoimmune cholestasis panel: antimitochondrial antibody and cholestatic enzymes.
6. Drug and alcohol history within three months.
7. Imaging of the bile ducts if the cholestatic pattern suggests it.
8. Hepatitis B virus status before any immunosuppressive therapy, with prophylactic antiviral prophylaxis for patients at high or moderate risk of reactivation during glucocorticoid use. ^[3]

Biopsy, with immunohistochemistry or copper stains where indicated, resolves most remaining uncertainty.

Management is lifelong for most patients. The aim is complete biochemical response: normalisation of alanine aminotransferase, aspartate aminotransferase and immunoglobulin G within 6 to 12 months (older AASLD 2019 and KASL 2022 texts set the target at 6 months). ^[2][3][4] Histological remission (hepatic activity index below 4) is the ideal endpoint and lags behind biochemical response, so treatment should not be stopped just because blood tests have normalised.

The AASLD suggests a two-week observation on glucocorticoid before adding azathioprine, to confirm steroid responsiveness and to test thiopurine methyltransferase activity. ^[2] The 2025 EASL guideline endorses mycophenolate mofetil as a first-line alternative to azathioprine and no longer lists budesonide for induction; the 2024 HASL guideline uses prednisolone with azathioprine or mycophenolate. ^[4] In East Asian populations, NUDT15 variants can predispose to azathioprine myelosuppression; TPMT and NUDT15 are the two genotypes usually considered, and where genotyping is unavailable a low starting dose with frequent early blood counts is a safe substitute. ^[3] Azathioprine is usually started at 50 mg/day and titrated to 150 mg/day or 2 mg/kg/day, with a full blood count monitored. ^[3]

Budesonide 9 mg/day combined with azathioprine produced higher six-month biochemical remission than prednisolone-based induction in non-cirrhotic patients (60 versus 38.8 percent) with fewer glucocorticoid side effects. ^[3] Budesonide must not be used in cirrhosis or acute severe hepatitis, because portosystemic shunting reduces its efficacy and increases systemic steroid effects. ^[1][3]

• Complete biochemical response: normal transaminases and IgG within 6 to 12 months.
• Insufficient response: lack of complete biochemical response by 6 to 12 months.
• Non-response: less than a 50 percent fall in transaminases within four weeks.
• Remission: hepatic activity index below 4.
• Intolerance: adverse event leading to possible drug discontinuation. ^[3]

Persistent elevation of AST or ALT under treatment predicts progression, including cirrhosis and hepatocellular carcinoma, even when the patient feels well. ^[3]

Once biochemical response is seen, prednisolone is reduced by 2.5 to 5 mg increments every 2 to 4 weeks to a maintenance of 5 to 10 mg/day, or the lowest dose that maintains response, while azathioprine is continued. Azathioprine alone (1 to 2 mg/kg/day) after steroid withdrawal sustains remission better than prednisolone alone and similarly to combination therapy. ^[3]

Withdrawal can be considered only after at least two years of complete biochemical remission (normal transaminases and immunoglobulin G). A liver biopsy before withdrawal is valuable for excluding unsuspected inflammation but is not mandatory in adults; it remains recommended in children. ^[1][3] Relapse is common: 20 to 46 percent even after two years of remission, most often within the first 6 to 12 months, and up to 80 percent of patients who stop too soon relapse. ^[1][3] Monitoring should be 3- to 6-monthly in the first year after withdrawal and every 6 to 12 months thereafter for life. ^[3] Relapse is usually silent, so early detection matters; it is managed by reinstating the original induction regimen. ^[3]

Mycophenolate mofetil or tacrolimus is used for treatment failure, incomplete response or intolerance. Mycophenolate (1 to 2 g/day) is preferred because of ease of use and side-effect profile, but tacrolimus (0.5 to 6 mg/day, with drug-level monitoring) performed better in patients with true non-response. ^[1][3] Cyclosporine, 6-mercaptopurine, 6-thioguanine and allopurinol are alternatives for azathioprine intolerance. ^[3] Mycophenolate is contraindicated in pregnancy because of teratogenicity. ^[3][4]

In acute severe disease, prednisolone (0.5 to 1 mg/kg/day) is effective and does not significantly increase infection; in acute liver failure with encephalopathy, direct evaluation for transplantation is more appropriate than prolonged steroid trials. Response must be assessed within 1 to 2 weeks, with transplantation if liver function does not improve. ^[2][3]

Pregnancy should ideally be planned after at least one year of biochemical remission. ^[1][3][4] Glucocorticoids and azathioprine are maintained throughout pregnancy and breastfeeding. ^[1][3] Mycophenolate mofetil is contraindicated and should be stopped at least six weeks before conception. ^[3][4] Active AIH carries obstetric risk (gestational diabetes, pre-eclampsia, preterm birth), and women with cirrhosis should be screened for varices by endoscopy before conception or in the second trimester. ^[1][3] Relapse clusters in the first three months postpartum, so follow-up must be close. ^[3]

Patients on glucocorticoids are at increased fracture risk when the daily dose exceeds 7.5 mg prednisolone or the cumulative dose exceeds 5 g in the past year. ^[3] Bone mineral density should be measured at baseline in adults with risk factors and repeated every 2 to 3 years of continuous glucocorticoid treatment. ^[1][3] Supplementation with calcium 1000 to 1500 mg/day (KASL 2022) or 1000 to 1200 mg/day (AASLD-derived Komori review) and vitamin D 400 to 800 IU/day is recommended, serum 25-hydroxyvitamin D measured at diagnosis and annually, and bisphosphonates added when osteoporosis is documented. ^[1][2][3]

Transplantation is indicated for decompensated cirrhosis or acute liver failure unresponsive to steroids. Five-year patient and graft survival after transplantation for AIH are roughly 79 and 73 percent respectively. ^[2] Recurrence after transplantation is 10 to 50 percent. ^[3] Glucocorticoids may be withdrawn gradually after transplantation. ^[2]

Untreated active AIH is serious: early series showed high mortality within years. With treatment, 5- and 10-year survival are about 90 and 88 to 91 percent; mortality estimates vary by source (about 7.1 and 10 to 32 percent at 5 and 10 years in KASL 2022, and about 10.5 percent 10-year liver-related mortality in the population-based analysis cited by HASL 2024). ^[3][4] Cirrhosis at presentation is the main driver of prognosis; failure to achieve biochemical response within 12 months, frequent relapse, older age and non-white ethnicity are adverse. ^[3] Histological inflammation persists in 46 percent of patients whose biochemistry has normalised for at least six months. ^[3]

Hepatocellular carcinoma must be kept in view. The pooled incidence in AIH is 3.06 per 1000 person-years, but 10.07 per 1000 in cirrhotic patients versus 1.14 per 1000 in non-cirrhotic patients, and up to 12.3 percent over a median 11 years when cirrhosis is present. ^[3] Patients with AIH-related cirrhosis should be considered for surveillance with ultrasound and alpha-fetoprotein every 6 months, especially when additional risk factors such as obesity, older age, alcohol or AIH-PSC overlap are present. ^[3][4] Long-term immunosuppression also raises the risk of extrahepatic cancer, including colorectal, lung and skin cancer, so standard screening guidelines should be followed. ^[3]

Children. First-line therapy is prednisolone 1 to 2 mg/kg/day (maximum 60 mg/day) with azathioprine added after two weeks, tapered to 2.5 to 5 mg/day. Withdrawal is considered only after 2 to 3 years of complete biochemical remission with a pre-withdrawal liver biopsy. ^[3]

Older adults. Disease may be asymptomatic and cirrhosis more frequent at presentation, and drug interactions or osteoporosis may complicate treatment; age alone is not a reason to withhold treatment. ^[3][4]

Drugs, supplements and herbals can produce a hepatitis that resembles AIH. The distinction matters because stopping the offending agent may be enough. The classic culprits are nitrofurantoin, minocycline, methyldopa and hydralazine. ^[3] Latency ranges from weeks to 12 months in most cases, although it can exceed 12 months with agents such as nitrofurantoin and minocycline; drug-induced autoimmune-like hepatitis itself often resolves within 6 months of drug withdrawal. ^[2][4] Features favouring drug-induced autoimmune-like hepatitis include female sex, a hypersensitivity response in about a third, normal or near-normal immunoglobulin G, histology resembling AIH with less fibrosis, and, importantly, no relapse after glucocorticoid withdrawal. ^[3] Immune checkpoint inhibitor hepatitis is usually steroid-responsive, lacks autoantibodies and typical AIH histology, and is managed differently. ^[2][3]

• Transaminases, bilirubin, hepatitis B surface antigen and hepatitis C antibody are the minimum tests; a manual antinuclear antibody or an affordable immunofluorescence screen can replace a comprehensive panel.
• A liver biopsy remains ideal but may be unavailable; in that case a therapeutic trial of prednisolone with close follow-up can be both diagnostic and therapeutic, with response confirming the diagnosis.
• Budesonide may not be available or licensed; prednisolone combined with azathioprine is the reliable default.
• Thiopurine methyltransferase and NUDT15 genotyping are expensive; a low starting azathioprine dose with weekly blood counts in the first month is a safe substitute.
• Where transient elastography or endoscopy is unavailable, clinical signs, platelet counts and simple scores guide cirrhosis and variceal assessment.
• Ursodeoxycholic acid, mycophenolate, tacrolimus and endoscopy may be scarce; refer early to a specialised centre for second-line therapy or transplantation.

• Abnormal liver function tests and jaundice
• Hepatocellular carcinoma and other liver masses
• Primary biliary cholangitis and primary sclerosing cholangitis (overlap syndromes)
• Drug-induced liver injury
• Viral hepatitis B and C
• Cirrhosis and its complications
• Osteoporosis and bone health on glucocorticoids
• Pregnancy in chronic liver disease